Intraocular iontophoretic device and associated methods

ABSTRACT

The present invention includes methods and devices for delivering an active agent into the eye of a subject. One such device may include an anode assembly having an anode housing and an anode configured to electrically couple to a power source, the anode assembly being configured to contact and remain against a surface of the eye. The device may also include a cathode assembly having a cathode housing and a cathode configured to electrically couple to the power source, the cathode assembly being configured to contact and remain against the surface of the eye. Additionally, the device may include at least one active agent reservoir functionally associated with at least one of the anode assembly and the cathode assembly.

PRIORITY DATA

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/729,980, filed on Oct. 24, 2005, which isincorporated herein by reference. This application also claims thebenefit of U.S. patent aqpplication Ser. Nos. 11/238,144 and 11/238,104,both filed on Sep. 27, 2005, both of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to systems, methods, and devices for thedelivery of an active agent following minimally invasive or noninvasivedelivery thereof through a localized region of a subject's body tissue,particularly the eye. Accordingly, the present invention involves thefields of chemistry, pharmaceutical sciences, and medicine, particularlyophthalmology.

BACKGROUND OF THE INVENTION

Posterior and intermediate eye diseases that require ocular drugdelivery to prevent blindness include uveitis, bacterial and fungalendophthalmitis, age-related macular degeneration, viral retinitis, anddiabetic retinopathy, among others. For example, the reported incidenceof posterior uveitis is more than 100,000 people in the United States.If left untreated, uveitis leads to blindness. It is responsible forabout 10 percent of all visual impairment in the U.S. and is the thirdleading cause of blindness worldwide.

Treatments of intermediate and posterior uveitis are complicated by theinaccessibility of the posterior eye to topically applied medications.Current therapy for intermediate and posterior uveitis requires repeatedperiocular injections and/or high-dose systemic therapy withcorticosteroids. Injections are usually preferred to systemic drugadministration because the blood/retinal barrier impedes the passage ofmost drugs from the systemically circulating blood to the interior ofthe eye. Therefore large systemic doses are needed to treat intermediateand posterior uveitis, which often result in systemic toxicitiesincluding immunosuppression, adrenal suppression, ulcerogenesis, fluidand electrolyte imbalances, fat redistribution and psychologicaldisorders.

Endophthalmitis affects approximately 10,000 people in the United Stateseach year. Endophthalmitis is typically caused by gram-positive bacteriaafter ocular surgery or trauma, but it can also be fungal or viral innature. The current method of treating endophthalmitis is directinjection of antimicrobials into the vitreous. Intravitreal injectionsare necessary because periocular injections and systemic administrationdo not deliver efficacious amounts of antibiotics to the target sites inthe eye. Age-related macular degeneration (AMD) is the leading cause ofirreversible loss of central vision in patients over the age of 50. AMDaffects more than 15 million people worldwide.

Treatments of posterior eye diseases require intravitreal and periocularinjections or systemic drug administration. Systemic administration isusually not preferred because of the resulting systemic toxicity asdiscussed above. While intravitreal and periocular injections arepreferable to systemic administration, the half-life of most injectedcompounds in the vitreous is relatively short, usually on the scale ofjust a few hours. Therefore, intravitreal injections require frequentadministration. The repeated injections can cause pain, discomfort,intraocular pressure increases, intraocular bleeding, increased chancesfor infection, and the possibility of retinal detachment. The majorcomplication of periocular injections is accidental perforation of theglobe, which causes pain, retinal detachment, ocular hypertension, andintraocular hemorrhage. Other possible complications of periocularinjections include pain, central retinal artery/vein occlusion, andintraocular pressure increases. Therefore, these methods of ocular drugdelivery into the posterior of the eye have significant limitations andmajor drawbacks. In addition, injections are very poorly accepted bypatients. These methods also involve high healthcare cost due to theinvolvement of skilled and experienced physicians to perform theinjections.

Ocular iontophoresis is a noninvasive technique used to delivercompounds of interest into the interior of a patient's eye. In practice,two iontophoretic electrodes are used in order to complete an electricalcircuit. In traditional, transscleral iontophoresis, at least one of theelectrodes is considered to be an active iontophoretic electrode, whilethe other may be considered as a return, inactive, or indifferentelectrode. The active electrode is typically placed on an eye surface,and the return electrode is typically placed remote from the eye, forexample on the earlobe. The compound of interest is transported at theactive electrode across the tissue when a current is applied to theelectrodes. Compound transport may occur as a result of a directelectrical field effect (e.g., electrophoresis), an indirect electricalfield effect (e.g., electroosmosis), electrically induced pore ortransport pathway formation (electroporation), or a combination of anyof the foregoing. Examples of currently known iontophoretic devices andmethods for ocular drug delivery may be found in U.S. Pat. Nos.6,319,240; 6,539,251; 6,579,276; 6,697,668, and PCT Publication Nos. WO03/030989 and WO 03/043689, each of which is incorporated herein byreference.

One potential problem with present ocular iontophoretic methods anddevices concerns the actual delivery, or rather, the non-delivery of thedrug into the eye tissue. Because the return electrode is located remotefrom the eye, various conductive pathways may be formed. Such divergenceof the electric current will decrease the efficiency of drug delivery tothe target sites in the eye, and as a result, much of the drug may bedelivered into the tissues surrounding the eye rather than into the eyeper se.

Additionally, despite its apparent advantages, iontophoresis is reallyjust a method of limiting the invasiveness of drug delivery into theeye's interior. Once inside the eye, the pharmacokinetics of watersoluble compounds are identical to those following intravitrealinjections i.e. their half-lives are on the order of a few hours.Therefore, in many cases, traditional iontophoresis must be repeated asfrequently as intravitreal injections, leading to patient inconvenience,increased costs, and increased possibility of untoward effects caused bythe iontophoretic treatment itself.

The problem of patient compliance may be compounded by the need toreceive daily treatment in a medical facility with high healthcare costsand limited resources and practitioners for treating retinal diseases.Existing ocular iontophoresis systems are not patent-friendly, requiremultiple parts and assembly to practice, and include either clumsy orcomplicated procedures. As such, they require the involvement ofexperienced healthcare professionals to perform the treatments.Paraprofessional and/or in-home self administration use of such devicesare precluded by the technical complexity of many existing iontophoreticdevices, as well as the costs of expensive dose-controlling equipment.Individuals have a greater tendency to deviate from a medication regimenwhen required to leave home for medical treatment, particularly whensuch treatment is frequent.

As such, devices, systems, and methods which are capable of minimallyinvasively, or non-invasively delivering drugs in a convenient,therapeutically effective manner, particularly to the interior of theeye, continue to be sought.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides devices and methods fordelivering an active agent into the eye of a subject, with only minimalinvasiveness. In one aspect, a device is provided for delivering anactive agent into an eye of a subject. Such a device may include ananode assembly having an anode housing and an anode configured toelectrically couple to a power source, the anode assembly beingconfigured to contact and remain against a surface of the eye. Thedevice may also include a cathode assembly having a cathode housing anda cathode configured to electrically couple to the power source, thecathode assembly being configured to contact and remain against thesurface of the eye. Additionally, the device may include at least oneactive agent reservoir functionally associated with at least one of theanode assembly and the cathode assembly.

Such an iontophoretic device may also be embodied as a self contained“all-in-one ” device. Accordingly, in one aspect a self-contained devicefor delivering an active agent into the eye of a subject is provided.Such a device may include a device housing, a first electrode assemblylocated at least partially within the housing and having a firstelectrode and a reservoir configured to contain the active agent, thefirst electrode assembly being configured to contact and remain againsta surface of the eye for a sufficient amount of time to deliver theactive agent to the eye, and a second electrode assembly located atleast partially within the housing and having a second electrodeconfigured to be opposite in polarity from the first electrode. Thedevice may further include a power source located at least partiallywithin the housing and electrically coupled to the first electrode andto the second electrode. Such a self-contained device may be configuredsuch that the power source, first and second electrode assemblies,conductive connections that electrically couple the power source to theelectrode assemblies, etc., are all located substantially or completelywithin the housing of the device. In some cases, the device may beconfigured such that the subject's eyelids may close substantiallycompletely thereover. In one aspect, the device may be configured as acontact lens. In another aspect, the device may be configured as ascleral lens or scleral shell.

Additionally, the present invention provides methods for delivery of anactive agent into the eye of a subject. For example, in one aspect amethod is provided for controlling delivery of an active agent to alocalized area in an eye of a subject. Such a method may includepositioning a device according to aspects of the present invention on aneye surface where the device has an inter-electrode distance between thefirst electrode assembly and the second electrode assembly that controlsthe depth and extent of penetration of the active agent within the eye,and iontophoretically delivering the active agent in the eye with thefirst electrode assembly. The active agent delivered into the eye mayprovide immediate therapeutic effect, sustained therapeutic effect, orboth immediate and sustained therapeutic effect.

The particular active agent to be delivered may be a variety ofsubstances depending on the particular treatment to be effected. Suchsubstances may include drugs in various forms, including prodrugsthereof, and sustained release formulations, as required in order toprovide convenient and effective minimally invasive, or non-invasivedelivery. Exemplary active agents are enumerated further herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front view of an iontophoretic device in accordance with anaspect of the present invention.

FIG. 2 is a front view of an iontophoretic device in accordance withanother aspect of the present invention.

FIG. 3 is a front view of an iontophoretic device in accordance with yetanother aspect of the present invention.

FIG. 4 is a front view of an iontophoretic device in accordance with afurther aspect of the present invention.

FIG. 5 is a front view of an iontophoretic device in accordance withanother aspect of the present invention.

FIG. 6 is a front view of an iontophoretic device in accordance with yetanother aspect of the present invention.

FIG. 7 is a cross sectional view of an iontophoretic device inaccordance with a further aspect of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Before the present systems and methods for ocular drug delivery aredisclosed and described, it is to be understood that this invention isnot limited to the particular process steps and materials disclosedherein, but is extended to equivalents thereof, as would be recognizedby those ordinarily skilled in the relevant arts. It should also beunderstood that terminology employed herein is used for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and, “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a polymer” includes reference to one or more ofsuch polymers, and “an excipient” includes reference to one or more ofsuch excipients.

DEFINITIONS

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

As used herein, “formulation” and “composition” may be usedinterchangeably herein, and refer to a combination of two or moreelements, or substances. In some embodiments a composition may includean active agent, an excipient, or a carrier to enhance delivery or depotformation.

As used herein, “active agent,” “bioactive agent,” “pharmaceuticallyactive agent,” and “pharmaceutical,” may be used interchangeably torefer to an agent or substance that has measurable specified or selectedphysiologic activity when administered to a subject in a significant oreffective amount. It is to be understood that the term “drug” isexpressly encompassed by the present definition as many drugs andprodrugs are known to have specific physiologic activities. These termsof art are well-known in the pharmaceutical, and medicinal arts.Examples of drugs useful in the present invention include withoutlimitation, steroids, antibacterials, antivirals, antiftingals,antiprotozoals, antimetabolites, immunosuppressive agents, VEGFinhibitors, ICAM inhibitors, antibodies, protein kinase C inhibitors,chemotherapeutic agents, neuroprotective agents, nucleic acidderivatives, aptamers, proteins, enzymes, peptides, and polypeptides.

As used herein “prodrug” refers to a molecule that will convert into adrug (its commonly known pharmacological active form). Prodrugsthemselves can also be pharmacologically active, and therefore are alsoexpressly included within the definition of an “active agent” as recitedabove. For example, dexamethasone phosphate can be classified as aprodrug of dexamethasone, and triamcinolone acetonide phosphate can beclassified as a prodrug of triamcinolone acetonide.

As used herein, “effective amount,” and “sufficient amount” may be usedinterchangeably and refer to an amount of an ingredient which, whenincluded in a composition, is sufficient to achieve an intendedcompositional or physiological effect. Thus, a “therapeuticallyeffective amount” refers to a non-toxic, but sufficient amount of anactive agent, to achieve therapeutic results in treating a condition forwhich the active agent is known to be effective. It is understood thatvarious biological factors may affect the ability of a substance toperform its intended task. Therefore, an “effective amount” or a“therapeutically effective amount” may be dependent in some instances onsuch biological factors. Further, while the achievement of therapeuticeffects may be measured by a physician or other qualified medicalpersonnel using evaluations known in the art, it is recognized thatindividual variation and response to treatments may make the achievementof therapeutic effects a subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

As used herein, “sclera” refers to the sclera tissue in the eye or theconjunctiva between the limbus and the fomix on the surface of the eye,which is the white part of the eye. “Sclera” is also used in referringto other eye tissues.

As used herein, “subject” refers to a mammal that may benefit from theadministration of a composition or method as recited herein. Examples ofsubjects include humans, and may also include other animals such ashorses, pigs, cattle, dogs, cats, rabbits, and aquatic mammals.

As used herein, “administration,” and “administering” refer to themanner in which an active agent, or composition containing such, ispresented to a subject. As discussed herein, the present invention isprimarily concerned with iontophoretic delivery, especially with oculardelivery.

As used herein, “noninvasive” refers to a form of administration thatdoes not rupture or puncture a biological membrane or structure with amechanical means across which a drug or compound of interest is beingdelivered. A number of noninvasive delivery mechanisms are wellrecognized in the transdermal arts such as patches, and topicalformulations. Many of such formulations may employ a chemicalpenetration enhancer in order to facilitate non-invasive delivery of theactive agent. Additionally, other systems or devices that utilize anon-chemical mechanism for enhancing drug penetration, such asiontophoretic devices are also known. “Minimally invasive” refers to aform of administration that punctures a biological membrane or structurebut does not cause excessive discomfort to the subjects and severeadverse effects. Examples of “minimally invasive” drug delivery aremicroneedle, laser, or heat punctuation in transdernal delivery andperiocular injections in ocular delivery.

As used herein, “depot” refers to a temporary mass inside a biologicaltissue or system, which includes a drug that is released from the massover a period of time. In some aspects, a depot may be formed by theinteraction of an active agent with a depot forming agent, such as acomplexing ion which will form an active agent complex that is lesssoluble than the active agent by itself, and thus precipitate in-vivo.

As used herein, the term “body surface” refers to an outer tissuesurface of the subject such as tissue surfaces encountered in ocular andtransdermal delivery, or mucosal tissues lining a body cavity such asthe mouth for buccal delivery or vaginal tract for vaginal delivery. Theterm “skin” refers to an outer tissue surface of the subject. It istherefore intended that skin also refer to mucosal and epithelialtissues, as well as the outer surfaces of the eye.

As used herein, the terms “electrode assembly,” “anode assembly,” and“cathode assembly” refer to an assemblies of at least one electrode anda housing at least partially surrounding the electrode. An electrodeassembly would thus include an electrode functioning as either an anodeor a cathode. Similarly, an anode assembly would include an anode, and acathode assembly would include a cathode. In some aspects, the housingmay be configured to form a reservoir to hold a substance to bedelivered to a subject, such as an active agent or a secondary compound.Such a housing may be made of a number of suitable materials. However,in one aspect, such a material may be an electrically non-conductive, orsemi-conductive material. In yet another aspect, the electrode assemblymay also include a barrier element configured to attach at a distalportion of the housing and therefore rest between the housing and theskin surface or tissue of a subject when the electrode assembly is inuse. Such barrier element can be made of an electrically non-conductivematerial, and in some aspects, such material will be different from thematerial of the housing. Examples of such materials include withoutlimitation, polymeric materials, such as adhesives or resins, rubbers,etc.

As used herein, the terms “anode” and “cathode” refer to the electricalpolarity of an electrode. The terms “anode” and “cathode” are well knownin the art. It should be noted, however, that in some aspects thesedescriptive terms may be transitory. When using alternating current, forexample, two electrodes will alternate between anode and cathode as thecurrent alternates in electrical polarity.

As used herein, the terms “reservoir” and “medicament compositioncontaining subcomponent” may be used interchangeably, and refer to abody or a mass that may contain an active agent, a depot forming agent,secondary compound, or other pharmaceutically useful compound orcomposition. As such, a reservoir may include any structure that maycontain a liquid, a gelatin, a semi-solid, a solid or any other form ofactive agent or secondary compound known to one of ordinary skill in theart. In some cases, an electrode may be considered to be a reservoir.

As used herein, the term “contact lens” refers to a lens sized to fitapproximately over the cornea of the eye.

As used herein, the term “scleral lens” refers to a lens sized to coverand extend beyond the cornea across at least a portion of the sclera ofthe eye.

As used herein, the term “active electrode” refers to an electrodeutilized to iontophoretically deliver an active agent.

As used herein, the term “passive electrode” refers to an electrode thatis used to complete an electrical circuit without delivering a compoundor substance to a subject.

As used herein, the term “return electrode” refers to an electrodeutilized to complete an electrical circuit for active electrode. In oneaspect, a return electrode may be an active electrode used to deliver asecondary compound, such as an active agent, a depot forming agent, etc.In another aspect, a return electrode may be a passive electrode.

As used herein, the term “self-contained” refers to a device thatcontains therein, or substantially therein, all the components requiredfor use. For example, a self-contained iontophoretic device may containactive agents, reservoirs, electrodes, power supplies, etc., within asingle housing.

As used herein, the term “reacting” refers to any force, change inenvironmental conditions, presence or encounter of other chemical agent,etc. that alters the active agent. For example, “reacting” between theactive agent and the depot forming agent can be physical or chemicalinteractions.

As used herein, the term “precipitate” refers to anything less thanfully solubilized. As such, a precipitate can include not only crystals,but also gels, semi-solids, increased molecular weight, etc.

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result. For example, an object that is“substantially” enclosed would mean that the object is either completelyenclosed or nearly completely enclosed. The exact allowable degree ofdeviation from absolute completeness may in some cases depend on thespecific context. However, generally speaking the nearness of completionwill be so as to have the same overall result as if absolute and totalcompletion were obtained. The use of “substantially” is equallyapplicable when used in a negative connotation to refer to the completeor near complete lack of an action, characteristic, property, state,structure, item, or result. For example, a composition that is“substantially free of” particles would either completely lackparticles, or so nearly completely lack particles that the effect wouldbe the same as if it completely lacked particles. In other words, acomposition that is “substantially free of” an ingredient or element maystill actually contain such item as long as there is no measurableeffect thereof.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 1 to about 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4,and from 3-5, etc.

This same principle applies to ranges reciting only one numerical value.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

The Invention

The present invention provides devices and methods for delivering anactive agent into the eye of a subject. In one aspect, a device isprovided for delivering an active agent into an eye of a subject. Such adevice may include an anode assembly having an anode housing and ananode configured to electrically couple to a power source, the anodeassembly being configured to contact and remain against a surface of theeye. The device may also include a cathode assembly having a cathodehousing and a cathode configured to electrically couple to the powersource, the cathode assembly being configured to contact and remainagainst the surface of the eye. Additionally, the device may include atleast one active agent reservoir functionally associated with at leastone of the anode assembly and the cathode assembly.

Such an iontophoretic device may also be embodied as a self containeddevice. Accordingly, in one aspect a self-contained device fordelivering an active agent into the eye of a subject is provided. Such adevice may include a device housing, a first electrode assembly locatedat least partially within the housing and having a first electrode and areservoir configured to contain the active agent, the first electrodeassembly being configured to contact and remain against a surface of theeye for a sufficient amount of time to deliver the active agent to theeye, and a second electrode assembly located at least partially withinthe housing and having a second electrode configured to be opposite inpolarity from the first electrode. The device may further include apower source located at least partially within the housing andelectrically coupled to the first electrode and to the second electrode.Such a self-contained device may be configured such that the powersource, first and second electrode assemblies, conductive connectionsthat electrically couple the power source to the electrode assemblies,etc., are all located substantially or completely within the housing ofthe device. In some cases, the device may be configured such that thesubject's eyelids may close substantially completely thereover. In oneaspect, the device may be configured as a contact lens. In anotheraspect, the device may be configured as a scleral lens or scleral shell.10054 The placement of both an anode assembly and a cathode assembly onthe surface of the eye may enhance penetration of the active agent intothe eye, as compared to devices which do not place both the anode andcathode assemblies on a surface of the eye, thus facilitating thelocalization of such agents in ocular tissues for the treatment ofvarious medical conditions. In addition to increased drug delivery dueto such novel placement of the anode assembly with respect to thecathode assembly, it has also been discovered that ocular drug therapymay be enhanced through increased patient compliance by providingmethods and devices that are easy to use and that may be utilized by anindividual at home. This can be accomplished by incorporating all of thephysical elements required for iontophoresis into a self-containeddevice. In some aspects, such devices may be intended for a single use,following which they may be disposed of, similar to many disposablecontact and scleral lenses. In addition to simplifying use, disposabledevices decrease the risk of infections and other eye-related conditionscommon to ocular procedures.

Prior methods of ocular delivery of an active agent often locate returnelectrodes remote from the eye. Such configurations are inconvenient andallow various conductive pathways to be formed across the tissuessurrounding the eye rather than focused only in the eye per se. Placingboth the anode assembly and the cathode assembly on the surface of theeye may facilitate the passage of electrical current transsclerally intothe eye under the anode and cathode, particularly when current movementacross the surface of the eye is limited. In one aspect, the anodeassembly and the cathode assembly may be respectively configured on thesurface of the eye such that the anode and the cathode complete anelectrical circuit substantially within the eye of the subject. In otherwords, the current between the anode and the cathode may passpredominantly through the eye tissues rather than into or through theconnective tissues surrounding the eye. In one aspect, both the anodeand the cathode may be oriented within the anode and cathode assembliesto face the surface of the eye. The anode and the cathode may directlycontact the surface of the eye, or they may contact the surface of theeye through an intermediate material or reservoir that is part of thedevice. In either case, such a “direct” contact between the electrodesand the eye surface may facilitate the focusing of electrical currentwithin the eye.

The relative spacing or the inter-electrode distance between the anodeand the cathode may play an important role in determining where anactive agent is localized in the eye upon delivery. As such, inaccordance with one aspect of the present invention, the anode and thecathode may be spaced at an inter-electrode distance which controls thedepth and extent of penetration of the active agent within the eye. Sucha spacing may focus the electric field more effectively within the eye,thus more effectively delivering the active agent. Increasing theinter-electrode distance will generally cause current to flow deeperinto the eye, thus iontophoretically delivering the active agent deeper.Small inter-electrode distances will cause a more superficial deliveryof active agent into the eye. Thus, by altering the physical locationsof each of the electrode assemblies, and thus the inter-electrodedistance between them, the active agent can be delivered to particularregions of the eye at specific depths. As such, the inter-electrodedistance may vary depending on the intended delivery location. In oneaspect of the present invention, however, the inter-electrode distancemay be less than about 40.0 mm. In yet another aspect, theinter-electrode distance may be from about 1 mm to about 10 mm. In afurther aspect, the inter-electrode distance may be from about 0.3 mm toabout 4 mm.

It is intended that an electrode assembly include at least oneelectrode. In some aspects, an electrode assembly may also include areservoir configured to contain an active agent or other compound to bedelivered. In other aspects, an electrode assembly may also include atleast one barrier element. For example, in one aspect an electrodeassembly may include an electrode, an electrically insulating barrierelement, and a reservoir configured to contain an active agent orsecondary compound. In another aspect, an electrode assembly may includean anode or a cathode and a reservoir.

The anode and cathode associated with the respective electrodeassemblies are intended to pass current due to a potential differenceestablished therebetween by a power source. The current acts to move anactive agent iontophoretically in a direction that is dependent on thecharge characteristics of the active agent and the charge orientation ofthe potential difference between the anode and the cathode. An activeelectrode, whether it be an anode or a cathode, is designed to deliverelectrical current across an associated reservoir to iontophoreticallydeliver the active agent located therein. In one aspect, one electrodemay be an active electrode and the other electrode may be a returnelectrode for merely completing the electrical circuit. For example, theactive electrode may be an anode and the return electrode may be acathode, or vice versa. In another aspect, one both the anode and thecathode may each have an associated reservoir for the delivery ofcompounds. The compounds may be the same or different, depending on theintended use and/or configuration of the device. In those aspects wherethe compounds are different, both compounds may be active agents, or onecompound may be an active agent and one compound may be a compoundhaving no known therapeutic effect. One example of a compound that mayhave no therapeutic effect is a depot forming agent. The anode and thecathode can be of the same or different size relative to each other.Also, the surface area of one or both electrodes can be configured tomodify their respective current densities when in use.

The anode and cathode can be of any material or manufacture known to oneskilled in the art. Various examples include metal electrodes,conductive glass electrodes, etc. A single electrode may be coupled to asingle reservoir or to multiple reservoirs depending on the particularconfiguration of a given electrode assembly. Conversely, multipleelectrodes having the same polarity may be coupled to a single reservoirin certain aspects. Additionally, in some aspects of the presentinvention, one of the electrodes may also be a reservoir, with asecondary compound being delivered from the body of the electrode.

The devices the present invention may include an electrically insulatingbarrier located between the anode and the cathode to preclude or reduceelectrical current flow across the surface of the eye. By preventingcurrent flow across the eye surface between the anode and the cathode,current is focused, or forced transsclerally into the eye to complete anelectrical circuit. In one aspect, the barrier element located on thedevice between the anode and the cathode and configured to contact thesurface of the eye. As such, the barrier element is configured toelectrically isolate the anode from the cathode at the surface of theeye. In another aspect, the barrier element may surround each of theanode assembly and the cathode assembly at the surface of the eye topreclude the passage of fluid and minimize current flow between theanode and the cathode. The barrier element may be constructed of anyelectrically inert material known that is capable of forming a barrier.The barrier element material may be the same material as the reservoirand/or the device housing, or it may be a different material selectedfor its dielectric properties. The barrier element may also bephysically coupled to the electrode assembly, or it may be a protrudingportion of a reservoir or a protruding portion of the device housing,and thus be continuous with the housing or reservoir. In those aspectswhere the barrier element is not continuous with the housing orreservoir, the barrier element may be comprised of a material that iseither the same or different from either the device housing or thereservoir material. Non-limiting examples of barrier element materialsmay include plastics, composites, nylons, polyesters, polyurethanes,polyethylenes, polycarbonates, etc. Barrier element materials may alsoinclude conductive materials such as metals provided the material isrendered non-conductive by coating or other means.

In one aspect, the barrier element may be a lip-seal, and it may form aseal substantially around each of the electrode assemblies. The distanceof the separation between the electrode assemblies may depend on thedielectric properties of the material disposed therebetween, and thusmay be highly variable. In one aspect, the separation may be from about0.05 mm to about 5 mm. In another aspect, the separation may be fromabout 0.1 mm to about 3 mm. In yet another aspect, the separation may befrom about 0.2 mm to about 1 mm. In a side-by-side electrode assemblyconfiguration, the distance of the separation between the reservoirs canalso be used to control the depth of the penetration and thedistribution of the agents in the tissue from the body surface.

In one aspect, electrical isolation can be accomplished by applying atemporary sealant between the electrical assemblies and the eye surface.In addition to directing electrical current through the tissue, such asealant may also advantageously function to temporarily affix and holdthe electrode assemblies in place on the body surface. Sealants may beany useful insulative material known to one skilled in the art, forexample and without limitation, gels, waxes, adhesives, impermeablepolymeric or resinous materials, etc.

The power sources of the present invention may be any component known toone of ordinary skill in the art that is capable of powering aniontophoretic device. Powering the iontophoretic device includesproviding an electrical current or an electrical potential facilitatingthe delivery of an active agent. In those aspects having power sourcesself-contained within the device housing, it may be beneficial for thepower source to be a flexible battery or the like. Conductivesubcomponents may be utilized to electrically couple the power source tothe anode within the anode assembly and to the cathode within thecathode assembly. These conductive subcomponents may include wires,traces, microelectronics, or other conductive materials such asconductive fluids within insulated tubing or channels. Suchmicroelectronics may be useful in controlling the delivery of the activeagent, and/or for safety purposes. Self-contained aspects mayparticularly benefit from configurations having the conductivesubcomponents substantially or completely embedded within the housingmaterial. In this way, the device allows the subject to blink fairlynormally, thus reducing the irritation of the administration of theactive agent, and thus increasing patient compliance. In another aspectof a self-contained device, any of the power source, electroniccircuitry, conductive subcomponents, etc., may be housed completely orpartially in a protruding portion of the device housing. Such aprotruding portion may include, for example, a handle used to manipulatethe device.

The reservoirs according to aspects of the present invention aredesigned to hold an active agent or other secondary compound to bedelivered prior to administration through the eye tissues of a subject.Such reservoirs are configured to receive electrical current from anelectrode to thus iontophoretically deliver an active agent or othercompound therefrom. In one aspect, a reservoir may be a distinctcompartment, having a lumen for holding an active agent or othersecondary compound to be delivered. Additionally, such a reservoir maycontain at least one access port to allow the reservoir to be filledwhile in contact with the body surface of the subject. Thisconfiguration may allow the reservoir to be filled during use as theagent within is depleted. In another aspect, a reservoir may be filledduring manufacture of the device with an active agent or other secondarycompound to be delivered, particularly in those aspects where the deviceis intended for a single use. Various iontophoretic reservoir materialsare known to those skilled in the art, and all are considered to bewithin the scope of the present invention. Additionally, the activeagent or secondary compound may be included in the reservoir in anyform, including, without limitation, a liquid, gelatinous, semi-solid,or solid form. In another aspect the reservoir may consist of a portionof the active electrode, such that an active agent or secondary compoundis delivered from the electrode when electrical current is introduced.

For optimal iontophoretic delivery of active agents and other compoundsinto the eye, a permselective material may be placed in ion-conductingrelation to the eye surface. An electric current of AC, DC, and AC withsuperimposed DC can be used to transport the compound of interestthrough the permselective material into the eye. The permselectivematerial is capable of hindering iontophoretic transport of a competingion and thus may increase the transference efficiency of the activeagent or other compound of interest during iontophoresis. As a result,the active agent may be delivered iontophoretically into the eye moreefficiently than iontophoresis without the permselective material. Forexample, more efficient iontophoretic transport can be achieved byplacing the permselective material against an active electrode (e.g.,Ag/AgCI) between the electrode and a reservoir to prevent the productsof electrochemical reactions generated at the electrode surface (e.g.,Ag or Cl ions) from moving into the reservoir. Another example is toplace the permselective material at the interface between the surface ofthe eye and the device. As such, the permselective material may belocated between the eye surface and the reservoir to prevent themigration of the active agent and endogenous ions into a reservoircontaining a secondary compound of opposite charge, or vice versa thesecondary compound and endogenous ions into the active agent reservoirduring iontophoresis. Any permselective material capable of hinderingiontophoretic transport of a competing ion during iontophoretictransport of the compound of interest may be used in conjunction withthe invention. The permselective material may be provided in any of anumber of forms as described in applicant's copending U.S. patentapplication Ser. No. 10/371,148 entitled “METHODS AND SYSTEMS FORCONTROLLING AND/OR INCREASING IONTOPHORETIC FLUX”, filed on Feb. 21,2003, which is incorporated herein by reference. For example, thematerial may be provided in a liquid, partially liquid, gelled,partially solid, or fully solid state. In some instances, thepermselective material may be supported by a support structure such asan additional membrane having sufficient porosity and chemical inertnessso as to avoid interfering with the performance of the permselectivematerial, yet having sufficient mechanical integrity for ease inhandling. The material can also be provided in the form of a membranehaving a surface sized and/or shaped for direct contact with the eye orshaped for direct contact with an active electrode (e.g., Ag/AgCl). Inother instances, the permselective material may be comprised of apolyelectrolyte, which can be a single molecule or an aggregate ofmolecules having ions or ionizable groups. Additionally, in one aspect apermselective material may be functionally coupled to an electrodedelivering an active agent or secondary compound, and/or to an electrodemerely completing the electrical circuit.

Numerous configurations for the housings of the devices of the presentinvention are contemplated, for both single-use and multiple-usedevices. In one aspect, the housing may be configured to allow theeyelids of the subject to close substantially completely thereover. Inother words, when the device is in contact with the eye, the subject maybe able to blink in a fairly normal fashion. Such devices may beconfigured to resemble a contact lens or a scleral lens. It is alsocontemplated that devices may be utilized that have irregular shapes,thus differing from the common circular and oval shapes of such lenses,such as half-moon or kidney shapes. In another aspect, the housing maybe configured to substantially enclose all conductive connectionsbetween the power source and both the return electrode assembly and theactive electrode assembly. In this manner, the device would allow simpleinsertion onto the surface of the eye, and would facilitatesubstantially normal eye closure and blinking during use. This isparticular advantageous in ocular iontophoresis that it provides aneasy-to-use all-in-one device and improves patient compliance,especially, when multiple applications are required. Additionally, inthose aspects where the device is self-contained, the distance betweenthe electrode assemblies and the power source is necessarily limited.For example, in one aspect the active electrode assembly and the powersource may be separated by a distance of less than 40.0 mm. In anotheraspect, the active electrode assembly and the power source may beseparated by a distance of less than 20.0 mm. In yet another aspect, theactive electrode assembly and the power source may be separated by adistance of less than 10.0 mm.

Various materials are contemplated for use as the housing that maysecurely hold the various components of the device while providingdielectric properties sufficient to maintain these components inelectrical isolation. It may be additionally beneficial to utilizematerials that provide some level of flexibility to avoid damage orirritation to the eye surface. Any material having properties beneficialto the construction of such a device would be considered to be withinthe scope of the present invention. For example, the housing materialmay include, without limitation, plastics, metals, composites, Teflon,nylons, polyesters, polyurethanes, polyethylenes, polycarbonates, etc.Materials such as metals may be utilized that are conductive, and thuswould need have dielectric materials incorporated therein in order tomaintain electrical isolation between various components of the devicethrough the housing.

The housing may also have an associated suction mechanism to createdepressurization between the device and the surface of the eye to holdthe device onto the eye during treatment. Such a suction mechanism mayeven hold the device in place during blinking. Depressurization mayoccur in a reservoir of the device or in a separate suction chamber.Following delivery of the active agent, the device can be pressurized atthe interface surface to allow release and subsequent removal. Controlof the pressurization and depressurization of the device may beincorporated into the device housing, into a manipulation handle, or anyother convenient location. Additionally, the depressurization may beaccomplished by the shape of the device housing alone. For example, adevice housing conforming to the surface of the eye may be depressurizedby merely applying pressure to the device. Removal of such a device may,however, be more problematic that a device having a means to controlpressurization, such as a valve element.

Various device configurations are contemplated that allow theiontophoretic administration of an active agent through the eye tissueof a subject in order to provide a therapeutic effect. For example,devices may be constructed wherein the electrode assemblies are in asingle integrated unit. In one aspect, the anode assembly and thecathode assembly may be configured adjacent one another within theintegrated single unit. Alternatively, devices may be constructed as acollection of separate electrode assemblies or arrays that function as asingle unit. As such, in one aspect of the present invention, a devicemay be a single integral unit to contain and deliver the active agent.Such a device may have separate electrode assemblies, one to deliver anactive agent and one to act as a return. In another aspect, bothelectrode assemblies may be used to deliver active agents and/orsecondary compounds. Each of these electrode assemblies may be placed incontact with the eye surface though which the active agent or secondarycompound is to be iontophoretically administered. Additionally, theshape of the device may be configured to conforn to an eye surface. Insuch a configuration, the electrode assemblies may be in contact withvarious tissue structures in the eye, such as the conjunctiva, limbus,cornea, etc. In one aspect, a portion of the device may cover the corneawith at least one reservoir or barrier element being in contact with theconjunctiva. The portion covering the cornea may provide a better fit ofthe device onto the eye. In another aspect, the device may extend intothe cul-de-sac under the eyelids for the same purpose. The portion ofthe device in the cul-de-sac can also hold an electrode assembly,electrode assemblies, or barrier elements in contact with theconjunctiva.

Various placement configurations of electrode assemblies arecontemplated. For example, in many cases side-by-side electrode assemblyconfigurations may be beneficial. Such a configuration may alloweffective iontophoresis at a target location while minimizing the extentof the movement of the electrical current in other parts of the body.This is particularly beneficial when administering an active agent tosensitive areas such as the eye, where potential adverse effects may becaused by excessive electrical current passing through particularlysensitive tissues such as the retina in the back of the eye, the opticnerve, etc. Numerous placement configurations are possible, and thosediscussed herein should not be seen as limiting. In one aspect theelectrode assemblies can be located side-by-side on the conjunctiva andsclera. In another aspect, one electrode assembly may be located in theinferior cul-de-sac and the other electrode assembly may be located inthe superior cul-de-sac. The active agent may be delivered to varioustissue regions depending on the relative locations of the electrodeassemblies, such as the sclera, conjunctival, subconjuctival space,ciliary body, choroids, retina, anterior chamber, vitreous, etc. Thepreferred site may depend on the site of drug action in the eye toprovide a pharmacological effect.

While administration to nearly any portion of the eye may be suitable,in one aspect, the active agent or secondary compound may be delivereddeeply within the eye by spacing the electrode assemblies relatively farapart. When electrical current is applied through the electrodes, theactive agent or secondary compound is released and travels in a movingfront through the electrical field. By spacing the electrode assembliesrelatively far apart the electric field will penetrate deeper into theeye tissue, and as such, the compound will be delivered substantiallydeeper into the eye. Delivering an active agent to the center of theglobe of the eye may be beneficial because such a location is fairlydistant from the vascular clearance beds of the retina and choroids,thus improving retention of the active agent. Such a deep delivery maybe accomplished by positioning one electrode assembly in the inferiorcul-de-sac and the other electrode assembly in the superior cul-de-sac,or vice versa. In another embodiment as an example, when the electrodeassemblies are placed on the pars plana next to the limbus, the site ofdelivery is preferably in the posterior chamber under the electrodes andthe anterior chamber. When the electrode assemblies are placed near thefomix, the site of delivery is the conjunctiva and sclera under theelectrodes.

Various side-by-side configurations for the electrode assemblies arepossible, depending on the desired delivery location of an active agent,the efficacy of a depot formation, the desired depot location, patientcomfort, the active agent/depot forming agent configuration, etc. In oneaspect, the electrode assemblies may be placed adjacent to each other,and may be of various shapes such as, without limitation, circles,ovals, triangles, squares, rectangles, polygons, trapezoids, etc.Adjacent may include any relative orientation such as superior toinferior, lateral to medial, or any diagonal combination thereof, as ismore fully described herein.

Referring now to FIG. 1, one embodiment of an iontophoretic device inaccordance with the present invention is shown. lontophoretic device 10is provided having a device housing 12 that is configured to conform theeye of the subject. The device 10 may include an anode assembly 14 and acathode assembly 16. The electrode assemblies can be spatially arrangedin any configuration relative to one another within the device housing12. Each of these electrode assemblies may be surrounded by a barrier 18to preclude conduction of current across the surface of the eye and thusfocus current into the eye. In one aspect, the electrode assemblies maybe present in the device housing without a surrounding barrier (notshown). One or more active agent reservoirs 19 may be associated with atleast one of the anode assembly 14 and the cathode assembly 16. FIG. 1shows the active agent reservoir 19 associated with the anode assembly.A power source 20 is located centrally within the device housing 12. Inanother aspect the power source may be located in the housing outside ofthe region 28 located over the eye's limbus, so as not to obstruct thevision of the subject. The power source 20 may include a negative pole22 electrically coupled to the anode assembly 14 via a conductive trace26 and a positive pole 24 electrically coupled to the cathode assembly16 via a conductive trace 26.

FIG. 2 shows an embodiment of an iontophoretic device 30 having a devicehousing 32 including two anode assemblies 34 and two cathode assemblies36. The electrode assemblies may be arranged in an annular arrangementas shown, or in any other arrangement that is beneficial to the deliveryof an active agent in a subject. The anode assemblies 34 may eachdeliver the same active agent or they may deliver different activeagents having similar charge, or one or both may merely act as returnelectrodes. Similarly, both cathode assemblies 36 can each deliver thesame or different active agents, or one or both may also merely act asreturn electrodes. Additionally, any of the electrode assemblies maydeliver a secondary compound. Each electrode assembly may be surroundedby a barrier 38 to preclude conduction of electrical current across thesurface of the eye. The device 30 additionally includes a power source20, a negative pole 22, a positive pole 24, conductive traces 26, andreservoirs (not shown) as described in FIG. 1.

FIG. 3 shows yet another embodiment of an iontophoretic device 40 havinga device housing 42 including two anode assemblies 44 and two cathodeassemblies 46. The electrodes assemblies may be spatially arranged alonga single axis as shown, or along multiple axes. The electrode assembliesmay be arranged in electrode assembly pairs, with each pair including ananode assembly 44 and a cathode assembly 46. As has been described, therelative locations of the electrode assembly pairs and the relativespacing of the electrode assemblies within the pairs may determine thedelivery location(s) of the active agent and any delivered secondarycompound. The anode assemblies 44 may each deliver the same active agentor they may deliver different active agents having similar charge, orone or both may merely act as return electrodes. Similarly, both cathodeassemblies 46 can each deliver the same or different active agents, orone or both may also merely act as return electrodes. Additionally, anyof the electrode assemblies may deliver a secondary compound. Eachelectrode assembly may be surrounded by a barrier 48 to precludeconduction of electrical current across the surface of the eye. Thedevice 40 additionally includes a power source 20, a negative pole 22, apositive pole 24, conductive traces 26, and reservoirs (not shown) asdescribed in FIG. 1.

FIG. 4 shows an additional embodiment of an iontophoretic device 50having a device housing 52 including four anode assemblies 54 and fourcathode assemblies 56 that locally interact to function as fourelectrode assembly pairs. As such, active agent can be delivered to atleast four locations within the eye. As shown, the conductive traces 26electrically couple each electrode assembly to the power source 20 so asto concurrently deliver active agent to at least four locations withinthe eye. In an alternative embodiment, conductive traces may beconfigured such that active agent is delivered to at least fourlocations consecutively, or in an alternating fashion. As such, theamount of electrical current concurrently delivered to the eye may belimited. As has been described in the previous FIGS., the relativelocations of the electrode assembly pairs and the relative spacing ofthe electrode assemblies within the pairs may determine the deliverylocation(s) of the active agent and any delivered secondary compound.Also, each electrode assembly may be surrounded by a barrier (not shown)to preclude conduction of electrical current across the surface of theeye. The device 50 additionally includes a power source 20, a negativepole 22, a positive pole 24, conductive traces 26, and reservoirs (notshown) as described in FIG. 1.

FIG. 5 shows another embodiment of an iontophoretic device 60 having adevice housing 62 including four anode assemblies 64 and four cathodeassemblies 66. The electrode assemblies may be arranged in an annulararrangement as shown, or in any other arrangement that is beneficial tothe delivery of an active agent in a subject. As has been discussed inthe previous FIGS., the anode assemblies 64 may each deliver the sameactive agent, different active agents having similar charge, or act asreturn electrodes. Similarly, the cathode assemblies 66 can deliver thesame or different active agents, or act as return electrodes. Eachelectrode assembly may be surrounded by a barrier (not shown) topreclude conduction of electrical current across the surface of the eye.The device 60 additionally includes a power source 20, a negative pole22, a positive pole 24, conductive traces (not shown), and reservoirs(not shown) as described in FIG. 1.

FIG. 6 shows yet another embodiment of an iontophoretic device 70 havinga device housing 72 including two anode assemblies 74 and two cathodeassemblies 76. The electrode assemblies may be arranged in a bullseyepattern as shown, or in any other arrangement that is beneficial to thedelivery of an active agent in a subject. As such, each electrodeassembly may be a complete or substantially complete circle, havingalternating anode and cathode assemblies nested within one another.Electrode assemblies may be activated concurrently to deliver activeagent simultaneously, or they may be activated consecutively. The numberof electrode assemblies shown in FIG. 6 is merely exemplary, and anynumber may be included in a particular aspect and still be within thescope of the present invention. As was described in the previous FIGS,each electrode assembly may be surrounded by a barrier (not shown) topreclude conduction of electrical current across the surface of the eye.The device 70 additionally includes a power source 20, a negative pole22, a positive pole 24, conductive traces (not shown), and reservoirs(not shown) as described in FIG. 1.

FIG. 7 shows one example embodiment of an iontophoretic device 80 havinga handle 82 to assist in the manipulation of the device 80. As has beenpreviously described, an iontophoretic device according to variousaspects of the present invention may be self-contained, and thus includewithin the housing all components necessary for the functioning of thedevice. It should be understood that such a self-contained device mayalso include aspects having components located within the handle thatare not required to be in contact or near the surface of the eye. Forexample, as shown in FIG. 7, a power source 84 may be located within thehandle 82 of the device 80. Conductive traces 86 may electrically couplethe power source 84 to the electrode assemblies (not shown) locatedwithin the device housing 88. Additional components that may be locatedwithin the device housing 88 may include, without limitation, conductivesubcomponents, suction manipulation devices, microelectronics, etc.

The present invention also includes methods for controlling delivery ofan active agent to a localized area in an eye of a subject. Such amethod may include positioning a device according to aspects of thepresent invention on an eye surface, with the device having aninter-electrode distance between a first electrode assembly and a secondelectrode assembly that controls the depth and extent of penetration ofthe active agent within the eye, and iontophoretically delivering theactive agent in the eye with at least the first electrode assembly. Sucha method may be performed to administer an active agent into the eye totreat various ocular and/or systemic medical conditions.

Though numerous conditions would benefit from the methods and devices ofthe present invention, they are particularly well suited for thetreatment of ocular diseases such as direct, combinatory, and adjunctivetherapies. This is because of the relatively high permeability of theeye tissues and the large aqueous compartments in the eye. Examples ofeye diseases include without limitation, macular edema, age relatedmacular degeneration, anterior, intermediate, and posterior uveitis, HSVretinitis, diabetic retinopathy, bacterial, fungal, or viralendophthalmitis, eye cancers, glioblastomas, glaucoma, and glaucomatousdegradation of the optic nerve.

Accordingly, a wide range of active agents may be used in the presentinvention as will be recognized by those of ordinary skill in the art.In fact, any agent that may be beneficial to a subject when administeredocularly may be used. Examples of the active agents that may be used inthe treatment of various conditions include, without limitation,analeptic agents, analgesic agents, anesthetic agents, antiasthmaticagents, antiarthritic agents, anticancer agents, anticholinergic agents,anticonvulsant agents, antidepressant agents, antidiabetic agents,antidiarrheal agents, antiemetic agents, antihelminthic agents,antihistamines, antihyperlipidemic agents, antihypertensive agents,anti-infective agents, antiinflammatory agents, antimigraine agents,antineoplastic agents, antiparkinsonism drugs, antipruritic agents,antipsychotic agents, antipyretic agents, antispasmodic agents,antitubercular agents, antiulcer agents, antiviral agents, anxiolyticagents, appetite suppressants, attention deficit disorder and attentiondeficit hyperactivity disorder drugs, cardiovascular agents includingcalcium channel blockers, antianginal agents, central nervous system(“CNS”) agents, beta-blockers and antiarrhythmic agents, central nervoussystem stimulants, diuretics, genetic materials, hormonolytics,hypnotics, hypoglycemic agents, immunosuppressive agents, musclerelaxants, narcotic antagonists, nicotine, nutritional agents,parasympatholytics, peptide drugs, psychostimulants, sedatives,steroids, smoking cessation agents, sympathomimetics, tranquilizers,vasodilators, 0-agonists, and tocolytic agents, and mixtures thereof.

Additionally, further examples of active agents may include steroids,aminosteroids, antibacterials, antivirals, antifungals, antiprotozoals,antimetabolites, VEGF inhibitors, ICAM inhibitors, antibodies, proteinkinase C inhibitors, chemotherapeutic agents, immunosuppressive agents,neuroprotective agents, analgesic agents, nucleic acid derivatives,aptamers, proteins, enzymes, peptides, polypeptides and mixturesthereof. Specific examples of useful antiviral active agents includeacyclovir or derivatives thereof.

Specific examples of active agents may also include hydromorphone,dexamethasone phosphate, amikacin, oligonucleotides, F_(ab) peptides,PEG-oligonucleotides, salicylate, tropicamide, methotrexate,5-fluorouracil, squalamine, triamcinolone acetonide, diclofenac,combretastatin A4, mycophenolate mofetil, mycophenolic acid, andmixtures thereof.

Under a number of circumstances, the active agent used may be a prodrug,or in prodrug form. Prodrugs for nearly any desired active agent will bereadily recognized by those of ordinary skill in the art. Additionally,prodrugs with high electromobility which metabolize into drugs with alow aqueous solubility may be beneficial. In this case, an electricallymobile prodrug of a low solubility drug in iontophoresis can be used tocreate a sustained release system in the eye. Because the prodrug hashigh electromobility, it is effectively delivered into the eye. Theprodrug then converts into the low solubility drug in the eye and theinsoluble drug precipitates in the eye. The drug in solid state in theeye will be slowly released into the eye and provide an ocular sustainedrelease condition.

Though any prodrug would be considered to be within the scope of thepresent invention, examples may include the derivatives of steroids,antibacterials, antivirals, antifungals, antiprotozoals,antimetabolites, VEGF inhibitors, ICAM inhibitors, antibodies, proteinkinase C inhibitors, chemotherapeutic agents, immunosuppressive agents,neuroprotective agents, analgesic agents, nucleic acid derivatives,aptamers, proteins, enzymes, peptides, polypeptides, and mixturesthereof. One specific example of a steroid derivative may includetriamcinolone acetonide phosphate or other derivatives of triamcinoloneacetonide, dexamethasone phosphate. For example, it may be preferable tolabel a steroid with one or more phosphate, sulfate, or carbonatefunctional groups, so the prodrug can be effectively delivered into theeye and form a complex with the precipitating ion.

In some cases, ocular treatment may be hampered by the in-vivomovement/clearance of the active agent in the eye. It is thereforecontemplated that various means for restricting or slowing such movementmay improve the effectiveness of the active agent therapy. In oneaspect, the in-vivo movement may be restricted by constriction of theblood vessels exiting an area in which the active agent is beingdelivered or precipitated. Such constriction may be induced by theadministration of a vasoconstricting agent. Such a vasoconstrictor maybe administered actively by iontophoretic or other means, or it may bedelivered passively. Specific non-limiting examples of vasoconstrictingagents may include α-agonists such as naphazoline, and tetrahydrozoline,sympathomimetics such as phenylethylamine, epinephrine, norepinephrine,dopamine, dobutamine, colterol, ethylnorepinephrine, isoproterenol,isoetharine, metaproterenol, terbutaline, metearaminol, phenylephrine,tyramine, hydroxyamphetamine, ritrodrine, prenalterol, methoxyamine,albuterol, amphetamine, methamphetamine, benzphetamine, ephedrine,phenylpropanolamine, methentermine, phentermine, fenfluramine,propylhexedrine, diethylpropion, phenmetrazine, and phendimetrazine.Vasocontricting agents can be administered either before or concurrentlywith the administration of the active agent. Though administration ofthe vasoconstrictor may occur following administration of the activeagent, the results may be less effective than prior or concurrentadministration. Additionally, in some aspects, the vasoconstrictingagent may have the same polarity as the active agent and administeredconcurrently with the active agent. Similarly, the vasoconstrictingagent may have the opposite polarity as active agent, and thus beadministered from a return electrode assembly.

Additionally, in another aspect of the present invention, in-vivomovement may be restricted by constriction of blood vessels as a resultof the application of physical force to the blood vessels.

It may also be beneficial for the application situs to be sealed with asealant following delivery of the active agent. This procedure mayprotect the tissue in which iontophoretic administration occurred.Sealants may include any known to one of ordinary skill in the art,including gels, glues and impermeable polymeric or resinous membranes.

Various treatment regimens according to aspects of the present inventionare contemplated. In one aspect, the administered active agent mayprovide an immediate therapeutic effect. In another aspect, the activeagent may provide a sustained therapeutic effect. In yet another aspect,the active agent may provide an immediate therapeutic effect and asustained therapeutic effect. In many cases, some form of sustainedrelease may be beneficial in order to reduce the frequency ofadministration. Such a reduction in administration may increase patientcompliance and reduce the frequency of eye infections and other relatedissues due to the decreased physical contact with the eye.

Various methods of providing sustained release, and therefore sustainedtherapeutic effect, are contemplated, some of which have been discussedherein. Such a sustained release may be due to a property of the activeagent, the use of a prodrug, the use of a sustained release depot, etc.In one aspect, a sustained release depot may be formed by the reactionof an active agent with a depot forming agent in the eye tissue,following delivery of the active agent to the subject. The depot formingagent may be delivered to the subject, or it may be an endogenoussubstance that reacts with the active agent. In either case, the depotforming agent and the active agent do not interact with one anotheruntil the active agent is delivered into the subject. As such, in mostcases the active agent and the depot forming agent will be separateduntil both are located in-vivo. If the depot forming agent is to bedelivered to the subject, then both agents should be deliveredseparately. Endogenous depot forming agents will, of course, not comeinto contact with the active agent until administration occurs. Thus anin-vivo reaction between the active agent and the depot forming agentwill cause the active agent or a derivative thereof to form a depot. Inone aspect such a depot forming mechanism may be a change in thesolubility of the active agent or a derivative of the active agent, thuscausing precipitation and subsequent depot formation. This depot ofactive agent complex is then able to deliver a therapeutic compound tothe biological system over time. Such sustained delivery can includelocal or systemic delivery of the active agent to the subject. As such,in one embodiment, a depot forming agent may be created at a desiredlocation in a subject, and the active agent may be systemicallyadministered and may “collect” at the depot forming agent to form adepot as the active agent circulates through the body. In anotheraspect, the depot forming agent may not react directly with the activeagent, but still functions to facilitate the formation of a sustainedrelease depot. In such a case, the depot forming agent may react with anarea of a local environment to cause an alteration therein. The activeagent would then react with the altered area of the local environment toform a depot as a result of the changes facilitated by the depot formingagent.

As a sustained release mechanism, it will be recognized that the depotformulation of the present invention generally has an in-vivo solubilitythat is lower than that of the active agent by itself. In this way, asthe active agent dissolves out of the depot over time, a sustainedtherapeutic effect may be obtained. Further, since the active agent inthe depot is unable to have a therapeutic effect until releasedtherefrom, the solubility properties of the depot limit potentialtoxicity or overdose concerns that would normally arise when deliveringa sufficient amount of drug to last over a prolonged period. Furtherdetails on such depot administration and depot agents can be found inU.S. patent application Ser. Nos. 11/238,144 and 11/238,104, both filedon Sep. 27, 2005, both of which are incorporated herein by reference.

It should be understood that the above-described arrangements are onlyillustrative of the application of the principles of the presentinvention. Numerous modifications and alternative arrangements may bedevised by those skilled in the art without departing from the spiritand scope of the present invention. Thus, while the present inventionhas been described above with particularity and detail in connectionwith what is presently deemed to be the most practical and preferredembodiments of the invention, it will be apparent to those of ordinaryskill in the art that numerous modifications, including, but not limitedto, variations in size, materials, shape, form, function and manner ofoperation, assembly and use may be made without departing from theprinciples and concepts set forth herein.

1. A device for delivering an active agent into an eye of a subject,comprising: an anode assembly having an anode housing and an anodeconfigured to electrically couple to a power source, said anode assemblyconfigured to contact and remain against a surface of the eye; a cathodeassembly having a cathode housing and a cathode configured toelectrically couple to the power source, said cathode assemblyconfigured to contact and remain against the surface of the eye; and atleast one active agent reservoir functionally associated with at leastone of the anode assembly and the cathode assembly.
 2. The device ofclaim 1, wherein the anode housing and the cathode housing arephysically coupled together.
 3. The device of claim 1, furthercomprising an electrically insulating barrier located between the anodeand the cathode and configured to contact the surface of the eye, suchthat the anode and the cathode are electrically isolated from oneanother across the surface of the eye.
 4. The device of claim 1, whereinthe anode assembly further comprises an active agent reservoir.
 5. Thedevice of claim 1, wherein the cathode assembly further comprises anactive agent reservoir.
 6. The device of claim 1, wherein the anode, andthe cathode are respectively configured so as to complete an electricalcircuit substantially within the eye of the subject.
 7. The device ofclaim 1, wherein the anode and the cathode are spaced at aninter-electrode distance which controls depth and extent of penetrationof the active agent within the eye.
 8. The device of claim 7, whereinthe inter-electrode distance is less than about 40.0 mm.
 9. The deviceof claim 7, wherein the inter-electrode distance is from about 1 mm toabout 10 mm.
 10. The device of claim 7, wherein the inter-electrodedistance is from about 0.3 mm to about 4 mm.
 11. The device of claim 1,wherein both the anode assembly and the cathode assembly are coupled toa device housing.
 12. The device of claim 11, further comprising a powersupply disposed at least partially within the device housing.
 13. Thedevice of claim 1, wherein at least one of the anode and the cathode isfunctionally coupled to a permselective material.
 14. The device ofclaim 13, wherein the permselective material is a membrane.
 15. Thedevice of claim 13, wherein the permselective material is in anion-conducting relation between the surface of the eye and the at leastone of the anode and the cathode.
 16. The device of claim 1, wherein theanode assembly is a plurality of anode assemblies and the cathodeassembly is a plurality of cathode assemblies.
 17. The device of claim16, wherein the plurality of anode assemblies and the plurality ofcathode assemblies are configured in a concentric orientation.
 18. Thedevice of claim 17, wherein the plurality of anode assemblies and theplurality of cathode assemblies are configured to alternate within theconcentric orientation.
 19. The device of claim 3, wherein theelectrically insulating barrier is in contact with conjunctiva of theeye.
 20. The device of claim 19, wherein a portion of the device coversthe cornea with the electrically insulating barrier in contact withconjunctiva.
 21. The device of claim 1, wherein a portion of the deviceis extended into a cul-de-sac under eyelids of the eye.
 22. The deviceof claim 1, wherein the anode assembly and the cathode assembly areconfigured adjacent one another within the device.
 23. A method ofiontophoretically delivering an active agent to an eye of a subject,comprising: positioning the device of claim 1 on the surface of the eyeof the subject; and activating the device to deliver the active agentinto the eye.